Lysosomal Acid Lipase (LAL) deficiency is a very rare lysosomal storage disease (LSD) characterized by a failure to breakdown cholesteryl esters (CE) and triglycerides (TAG) in lysosomes due to a deficiency of the enzyme. LAL deficiency resembles other lysosomal storage disorders with the accumulation of substrate in a number of tissues and cell types. In LAL deficiency substrate accumulation is most marked in cells of the reticuloendothelial system including Kupffer cells in the liver, histiocytes in the spleen and in the lamina propria of the small intestine. Reticuloendothelial cells express the macrophage mannose/N-acetylglucos amine receptor (also known as macrophage mannose receptor or MMR, CD206), which mediates binding, cell uptake and lysosomal internalization of proteins with GlcNAc or mannose terminated N-glycans, and provides a pathway for the potential correction of the enzyme deficiency in these key cell types.
LAL deficiency is a multi-system disease that most commonly manifests with gastrointestinal, liver and cardiovascular complications and is associated with significant morbidity and mortality. The clinical effects of LAL deficiency are due to a massive accumulation of lipid material in the lysosomes in a number of tissues and a profound disturbance in cholesterol and lipid homeostatic mechanisms, including substantial increases in hepatic cholesterol synthesis. LAL deficiency presents of at least two phenotypes, Wolman Disease (WD) and Cholesteryl Ester Storage Disease (CESD).
Wolman Disease is the most aggressive presentation of LAL deficiency. This phenotype is characterized by gastrointestinal and hepatic manifestations including growth failure, malabsorption, steatorrhea, profound weight loss and hepatomegaly. Wolman Disease is rapidly progressive and fatal usually within the first year of life. Case report review indicates survival beyond 12 months of age is highly unusual for patients who present with growth failure due to LAL deficiency in the first year of life. In this most aggressive form, growth failure is the predominant clinical feature and is a key contributor to the early mortality. Hepatic involvement as evidenced by liver enlargement and elevation of transaminases is also common in infants. Physical findings include abdominal distention with hepatomegaly and splenomegaly, and radiographic examination often reveals calcification of the adrenal glands. Laboratory evaluations typically reveal elevated levels of serum transaminases and absent or markedly reduced LAL enzyme activity. Elevated blood levels of cholesterol and triglycerides are also seen in patients.
Current treatment options for Wolman Disease are extremely limited. Antibiotics are administered to infants with pyrexia and/or evidence of infection. Steroid replacement therapy for adrenal insufficiency and specialized nutritional support may be prescribed and while there is no evidence that these interventions prevents death, it is also unclear at present if they have an impact on short term survival. In a series of four patients with LAL deficiency treated with bone marrow transplantation, all four patients died due to complications of the procedure within months of transplantation.
Patients with LAL deficiency can also present later in life with predominant liver and cardiovascular involvement and this is often called Cholesteryl Ester Storage Disease (CESD). In CESD, the liver is severely affected with marked hepatomegaly, hepatocyte necrosis, elevation of transaminases, cirrhosis and fibrosis. Due to the increased levels of CE and TG, hyperlipidemia and accelerated atherosclerosis are also seen in LAL deficiency. Particularly, an accumulation of fatty deposits on the artery walls is described early in life. The deposits narrow the arterial lumen and can lead to vessel occlusion increasing the risk of significant cardiovascular events including myocardial infarction and strokes. The presentation of CESD is highly variable with some patients going undiagnosed until complications manifest in late adulthood, while others can have liver dysfunction presenting in early childhood. CESD is associated with shortened lifespan and significant ill health; the life expectancy of those with CESD depends on the severity of the associated complications.
Current treatment options for the CESD phenotype are focused on controlling lipid accumulation through diet that excludes foods rich in cholesterol and triglycerides and suppression of cholesterol synthesis and apolipoprotein B production through administration of cholesterol lowering drugs. Although some clinical improvement may be seen, the underlying disease manifestations persist and disease progression still occurs.
In most cases, therapy for LAL deficiencies requires life-long treatment. In addition, due to the high cost of protein therapeutics, it is desirable to administer a minimum effective amount of therapeutic to treat LAL deficiency. However, to date, there is no effective therapy for treating LAL deficiency, particularly the patients suffering from Wolman Disease and CESD. Therefore, there is a strong need for an effective therapy with a minimized frequency of administration in order to improve the quality of life for patients. There is also a need for a high expressing and robust protein production platform which can produce LAL proteins that are stable and efficiently targeted to the lysosomal compartment in the affected tissue cells in patients.